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vii



United. States Patent 3,301,ss BENZOQUINOLIZINE PROCESS FOR PREPARINGSAME Claims priority, application Great Britain, July 8, 1959,

23,522/59 Claims. (Cl. 260-286) This application is a division ofapplication Serial No. 40,200, filed July 1, 1960, now US. Patent No.-3,121,720, granted February 18, 1964. a

This invention concernsa novel process for the production ofintermediates of use in the' productionof alkaloids and relatedcompounds of the isoquin'oline series and to the novel intermediates insuch processes. More particularly but not exclusively the invention isconcerned with novel methods for the synthesis of l-substituted-tetrahydro isoquinolines and other compou'nds of related structure. r v

Alkaloids and related synthetic compounds of the isoquinoline series, inparticular those-containing the benioquinolizine ring structure, arewell knownin chemotherapy. Thus, for example, the alkaloid emetine iswidely used in Asia and Africa to combat amoebic dysentery. Otherrelated compounds include cephaleine, psychoterine and emetamine, whiledehydroemetine has been reported as having useful pharmacologicalactivity. It'is thus an object of the invention to provide new methodsuseful in the preparation of 'pharmacolog'ically active compoundspossessing the basic benzoquinoliz'ine ring structure as well as otheruseful compounds. 9

Our new synthetic process is based upon, the initial reaction of adihydroisoquinoline with a compound containing a reactive methine group,that is, a group CH-Y where Y is a group able to activate the hydrogenatom of the CI-I Y group..- i Compounds containing reactive methinegroups are well known inchernistry being used in various reactions, thehydrogen atoms of such methine groupsbemga-ctivated by anelectronegative group which is frequently a carbonyl or cyano group.

It will be appreciated that wherea compound possesses two reactivemethine groups it is possible to reactone molecule of compound II withtwo molecules of the dihydroisoquinoline. Preferably the two reactivemethine groups are equally activated as in a symmetrical compound suchasacetone dicarboxylic acid. v Thus III (where the groups Y areactivating groups such as carbonyl groups).

As used in this specification,'the term reactive methine group of courseincludes reactive methyl and methylene groups.

According to'the present invention, therefore, we provide a process forthe preparation of 1-substituted 1,2,3,4-

tetrahydroisoquinolines in which a 3,4-dihydroisoquinoline compound isreacted with a compound XH, the hydrogen atom of which together with thecarbon atom to which it is attached constituting a reactive methinegroup, Whereby the group X adds onto the l-positionof the saiddihydroisoquinoline. K

, The compound XH is preferably of the general formula R'RCH.COR" whereR', R' and R" are organic.

groups, R being preferably a hydrogen atom.

As indicated above, when bis-isoquinolinoid derivatives are required,the compound XH should carry a further active methine group the hydrogenatom of which is activated so that on reaction with thedihydroisoquinoline the methine carbon atoms are attached to separatetetrahydroquinoline moieties.

In order to produce compounds possessing the benzoquinolizine ringstructure referred to above, the l-substituent may be cyclisedconveniently with an appropriate group introduced onto the N-atom.

. Thus, for example, the compounds of Formula III may then be reactedwith an appropriate compound to introduce onto the nitrogen atom a groupwhich undergoes ring closure with the group attached at the l-position.

I Illustratively, where the active methine compound is a carbonylcompound of formula RCH --COR (where R and R are organic groupings) theresulting compound will have the general formula R-O H-OOR III H a, k.

which on cyclisation forms a mixture of cyclic amides of formulaPatented Jan. 31, 1967' and may rearrange to give compound V in whichthe double bond is conjugated with the aromatic system. The double bondof compounds V and V may be reduced, together with the amide grouping togive a compound of skeletal 20 4 ketone R COCH=CH (where R is an organicgroup) gives rise to a compound of formula-- I VII which on ring closuregivesa cyclic alcohol of formula structure R OH VIII 4 v 6 3 Compounds Vand VIII in the above synthetic routes 7 2N 25 may also be converted tounsaturated alkaloids such as 8 dehydroemetine which has recently beensynthesised by Brossi et a1. (Helv.. Chem Acta, 42, 772 1959 and R-CH30H which is claimed to possess biological activity at least as great asemetine. Thus compound VIII may be subjected & 30 to Wolf-Kischnerreduction to reduce the keto group to methylene.

By way of example, the application of the above reacnamely the requiredbenzoquinolizine ring system.

Reaction of a compound of Formula III With a vinyl 35 i cyclisaw/ CHQO(d) removal of butyryl group and reduction of CHSO conjugated amide i|3=0 I B aC-CzHa CHaO tion sequence to the specific problem of thesynthesis of emetine takes place by alternatives (1) and (2) as follows:

(1) Via acid anhydride route:

Emetlne ketone H CI I Nornomooorn GHaC- -XII l-icyclisation NCHgCHzC OOH:

XIIIa A) dehydration I! CH30 k Q (h) removalot -CH2OH C OCH; group WEmetme a re ll OHaO" N c njugated amide 7 COCH3 I CH1 CH3) N-OHr-OHzO 0onoH3o ' XIII Inf route (1) -the cyclisation step (0) may give risewhich has been shown to have Reserpine-like activity (of. to the 1x25unsaturated'compounds XI shown, in admix- A. :Pletscher 'and H.Besendorf, Science, 1959, 129, 844). tu're with the respectivevat-unsaturated compound The routes outlined above provide a convenientmethod (herein designated compound XIA) and possibly also the for thesynthesis of com-pounds analogous to this, for [3-hydroXy saturatedcompound. (herein designated comexample by the following reactionscheme; a pound XIB). The 1125 and :6 unsaturated compounds may bereduced, after removal ofthe butyryl group, to

emetine but. the .B-hydroxy saturated compound should 9 be dehydrated togive one or both of the unsaturatedcom- N pounds, preferably afterisolation, before. proceeding as -9* described above.

- i V v Another benzoquinolizine derivative which possesses valuablepharmacological properties is the compound of i a CHsOOOH formula .t v

Methylvinyl I MeO-r v NH. ketone MeO-- I I Q i v .l

' /OH: 0 v Cfir-CH CHa CHa I I HO Et 4 t v,

' Cyclisationl XIV a MeO- COOH:

HO OH;

XVII

As can be seen compounds of the Formula III as well as compounds ofFormulas IV-VIII inclusive, all of which compounds are novel, representvaluable intermediates for the synthesis of various alkaloids andcompounds of interest.

We will now describe in detail the reactions involved in the processesaccording to the invention.

The reaction of dihydroisoquinoline (1) with reactive methyl ormethylene compounds.

For this reaction 3 :4-dihydroisoquinoline or substitution productsthereof having one or more substituents in the 3,4,5,6,7 and/or8-position may be used. The nature of the substituents should of coursebe such as not to react with the reactive methylene compound and will bechosen having regard to the nature of the substituent or substituentspresent in the alkaloid or other compound it is desired to synthesise.Suitable substituents are thus for example alkyl, aralkyl, aryl,alkenyl, alkoxy, aralkoxy, aryloxy, nitro, hydroxyl, thio, alkyl,aralkyor 'aryl thio, carboxyl, carbalkoxy, acyl or tertiary amino groupsor halogen or hydrogen atoms. substituents may be also occupy more thanone position, as in methylene dioxy groups. The 3 and 4 positions may ingeneral carry any of the above groups where the other reactant isacetone dicarboxylic acid, but with acetone it is preferable that the 3and 4 positions be unsubstituted or carry only substituents which do notreduce the electron attraction of the 2 nitrogen atom. Keto groups arepreferably not present in the 3 or 4 positions since the 3 and 4-ketonesare equivalent to 3 and 4-hydroxy isoquinolines which do not react withreactive methylene groups. The 1 position is preferably unsubstituted.substituents which cause steric hindrance at the site of reaction arealso to be avoided: thus, large groups in the 8-position tend to hinderthe reaction.

Preferred groups in the aromatic ring are alkoxy and methylenedioxygroups, especially methoxy groups in the 6- and 7-positions.

For the specific purpose of synthesising emetine the 6:7dimethoxy-3:4-dihydroisoquinoline is used.

The reactive methine compound XH can be any compound having a methyl,methylene or methine group activated, for example, by an adjacentcarbonyl group, nitrile, nitro group etc. such that the hydrogen atom ofthe methylene group is labile and compounds of this nature are of coursewell known to those skilled in the art. It is generally found that amethine group activated by a single activating group reacts only weaklywith the dihydroisoquinoline and that compounds having two groupsactivating the methine group are more reactive. This acetoacetic acid ismore reactive than ethyl acetate, which scarcely reacts at all, andacetone dicarboxylic acid is more reactive than acetone.

Illustrative of reactive methine compounds are ketones such as acetone,acetylacetone, keto acids, e.g. acetone dicarboxylic acid, acetoaceticacid, various esters, e.g. malonic esters, keto acid esters, certainacids such as malonic acid and cyanides, e.g. benzyl cyanide.

In the case of emetine and its analogues, acetone or acetonedicarboxylic acid may be used to form the bisadduct, compound IXdescribed above.

This reaction is preferably carried out in the presence of a solventmedium and advantageously also in the presence of an acid. Where acetoneis one of the reactants, an excess of this substance may serve asreaction medium. Further, since acetone dicarboxylic acid isconsiderably more reactive than acetone, when this acid is reacted with6:7 dimethoxy-3:4-dihydroisoquinoline, it is possible to use acetone asreaction medium, although other solvents, for example, pyridine oralcohols such as methanol may be used. Water may also be present. Asstated above, it is generally advantageous to carry out the reaction inthe presence of acid, although this is not essential since a high yieldof compound IX may be obtained in aqueous methanol without added acid.

The solvent system in which this reaction is carried out appears to havea profound effect upon the efliciency of the reaction, as does also theratio of the reactants and the presence or absence of added acid. Thus,where 6:7 dimethoxy-3:4-dihydroisoquino and acetone dicarboxylic acidare reacted in acetone in equimolar quantities at room temperature nocompound IX can be isolated, although it is possible to isolate themono-acetone adduct compound XV above which is a valuable intermediate.

Acylation and chromatography to recover the NN diacyl derivativehowever, leads to a 15% yield. On the other hand, it is often the casethat an intermediate compound is precipitated, again in about 15% yield,which compound gives compound IX on heating with dilute alkali and isprobably a carboxylated derivative. Acetylation or butyrylation of thisintermediate leads to the diacetyl or dibutyryl derivative of compoundIX, so that the intermediate can, if desired, be used in the synthesisof emetine by the butyrylation method. In pyridine the reactants inequimolar ratio give only a product which cannot be isolated but whichgives an acyl derivative of compound IX on acylation.

In both acetone and pyridine the use of the stoichiometric ratio of thereactants, namely 2 mols. 6:7 dimethoxy-3:4-dihydroisoquinoline to 1mol. acetone dicarboxylic acid, appears to give no isolatable compoundIX but if the reactants are reacted in the stoichiometric ratio inpyridine, and sulphuric acid is added as catalyst, it is possible toobtain as much as 32 to 40% of compound IX.

In acetone, using equimolar quantities of the reactants and usingsulphuric acid as a catalyst, the yield is about 30%.

The reaction appears to run more smoothly if water is present and thusin 25% aqueous acetone with added sulphuric acid and the 2:1 ratio ofthe dihydroisoquinoline to acetone dicarboxylic acid, as much as 60% ofcompound IX can be obtained while in aqueous methanol with the 2:1 ratioand without added acid the reaction is very smooth and again yields asmuch as 60% compound IX.

The addition of acid does appear to be beneficial, however, since in 80%aqueous methanol with the 2:1 ratio of reactants and added hydrochloricacid approximately 70% of compound IX may be obtained.

In all the methods discussed above for the production of compound IX,the final product has been a mixture of isomers. Since compound IXpossesses two asymmetric carbon atoms, namely the l-carbon atoms of eachof the tetrahydroisoquinoline rings, and is symmetrical about thecentral carbonyl group, two stereoisomeric forms exist, namely a racemicmixture of dextroand laevo-rotatory optical isomers, and the meso form.

Emetine itself exists in sixteen optically active forms since, inaddition to the two asymmetric carbon atoms derived from compound IX, italso possesses two further asymmetric carbon atoms in the additionalring.

In the synthesis of any given stereoisomeric form of emetine it isnecessary to start from a single form of compound IX and where apreparative method leads to a mixture of the isomers of compound IX,these should desirably be separated.

Separation may conveniently be efiFected by taking advantage of thediffering solubilities of the hydrochlorides of the two principal stableforms of compound IX. For convenience, the two stereoisomers of compoundIX are designated A and B and we. have proved that A is the racemic andB the Meso form. Recent determinations of the absolute configuration ofErnetine (eg. A.R. Battersby and S. Garratt, Proc. Chem. Soc., 1959, 86)suggest that the Meso form of (IX) corresponds to natural Emetine.

We. find that the hydrochloride of compound IXA is substantiallyinsoluble in ethanolic hydogen chloride while that of compound IXB issoluble and this solubility difference can be used to separate a mixtureof the two forms. It is also possible to add saturated ethanolichydrogen chloride to the reaction mixture to precipitate compound IXAhydrochloride directly.

I the A form.

Thus, when 6: 7 -.dimethoxy 3 :4 dihydroisoquinoline is reacted in 2:1ratio acetone dicarboxylic acid in 80% aqueous methanol in the presenceof sulphuric acid the initial product is an intermediate precipitatewhich on resuspension at pH 10 in aqueous sodium bicarbonate yieldscompound IXB. The remaining reaction solution can be worked up to give amixture of compounds IXA and IXB. The intermediate precipitate appearsto be a sulphuric acid salt of compound IXB.

Compound D(A can also be converted in good yield into IXB, by suspendingIXA in aqueous sulphuric acid, whereby it is gradually converted to thecompound described above which on treatment with base as before thengives compound IXB.

The isomers of Compound IX can be converted to isomers emetine by eitherof the routes described above, that is by the acid anhydride route or bythe vinyl ketone route.

Referring to the reaction sequence given above for the acid anhydrideroute, step (b) in that route may be carried out, in any convenient way,for example by reaction of compound IX with butyryl chloride in thepresence of an acid binding agent. We have found that butyric anhydridein the presence of pyridine, however, is particularly convenient and isable to acylate the nitrogen atom in almost quantitative yield.

Referring to the reaction sequence given above for the vinyl ketoneroute, step (e) which comprises the reac-. tion of methyl vinyl ketonewith compound IX may be carried out in any convenient way; the reactionis, in general, quite facile and may often be carried out in the absenceof catalyst e-.g. by simply mixing the reactant compounds in a commonsolvent. f

Referring to the cyclisation steps (c) and (f) in the two reactionroutes, the cyclisation can be effected in principle with alkaline oracidic catalysts, suitable alkaline catalysts being, for example, alkalimetal alkoxides, e.g. sodium methoxide, potassium t-butoxide etc. andsuitable acid catalysts being strong acids e.g. hydrochloric acid,sulphuric acid etc. The conditions for effecting the cyclisation varyfrom case to case, however, as explained hereafter. Step in the acidanhydride route, the cyclisation step may be carried out under theconditions generally used" for condensation of a carbonyl group with areactive methylene group. In this case the reactive methylene group isthat adjacent to the N-acyl carbonyl group. The cyclisation ispreferably carried out in the presence of a cyclising agent.

The nature of the cyclising agent influences the composition of themixture of cyclic amides produced. We find that in this cyclisation,alkaline cyclising agents are advantageous and produce predominantlyunsaturated cyclic amides. We have further found that strong cyclisingagents, such as potassiumtertiary butoxide, tend to produce more:6-un'saturated amide than atfi-unsaturated amide while weaker agentsproduce more a:,B

compound.

Step (1) in the vinyl. ketone route, the cyclisation step,againcomprises reaction of a carbonyl group with a reactive methylenegroup. In this case the methylene group is activated by the adjacentcarbonyl group of the acetyl group in the acetyl ethyl side chain. Thecyclising agent in the cyclisation of mono-tetrahydroisoquinolylderivatives may in general be, for example, hydrochloric acid or analkaline reagent such as sodium methoxide.- .We have found thathydrochloric acid-tends to produce larger quantities of theB-hydroxysaturated compound than do alkalinic reagents. Further, alkaline reagents under mild conditions, for example sodium methoxide in benZene atroom temperature, produce predominantly fl-hydroxy saturated productswhile under vigorous conditions, for example sodium methoxide underreflux, they produce predominantly the mil-unsaturated compound.Although the carbonyl, group of the acetylethyl side chain is alsocapable of reacting with the methylene groups on either side of thecarbonyl group which originally derived from acetone or acetonecarboxylic acid, the compounds described appear to be the principalproducts.

The bis-tetrahydroisoquinolyl derivatives e.g. compound XII, however,tend to give polymeric material under vigorous conditions andcyclisation is preferably achieved under very mild alkaline conditionsto yield a cyclic al- Preparation of the B isomer ofa-bis(1-:213:4-tetrahydr0 6:7-dimeth0xyisoquinol-1-yl) acetone (compoundIX) 3:4 dihydr o 6:7 dimethoxyisoquinoline (18.0 g.)

was dissolved in methanol (36.0 ml.) and Water (144.0 inl.) added. Tothis solution was added a solution of acetone dicarboxylic acid (7.2 g.)in aqueous sulphuric acid (cone, sulphuric acid(1.8 ml.)'in water 36.0ml.) A steady evolution of carbon dioxide occurred and the mixture wasallowed to stand at room temperature for 18 hrs. During this time asolid separated from solution. The reaction mixturewas dilutedwith'water and'this solid (13 precursor) filtered off. The wet solid wassuspended-in water (250 ml.) and the mixture adjusted to pH =10 by theaddition of aqueous sodium. carbonate; The resulting White suspensionwas stirred at room tern perature for 2 hours, then the solidfiltered,washed with water,. anddried at room temperature-invacuo overadessicant, to give 10.92 gpof compoundIXB 52.7% theory) M.P. 14 -149Found: C, 67.81; H, 7.53; N, 6,32%. quires C,68.16; H, 732; N, 6.36%.The aqueous solution remaining, after the removal of B precursor byfiltration, can be worked'up to yield a further amount'of mixedcompounds IXA and B in the following way. Aqueous sodium carbonate wasadded to adjust the pH 10, and the solution was extracted with methylenechloride (3X 75 ml.). The first two extracts were combined and washedwith water (3 x- 150 ml.) the water washes being back extracted with thethird methylene chloride extract. Removal of all the solvent in vacuofrom the combined methylene chloride extracts left a'pale'red oil, whichwas triturated with'warm ether and dried in vacuo at'room temperature'togive an additional 341 g. (16% theory)'of crude mixed compound IXA and Bisomers, M.P. 11 4- The B precursor, on drying, has M.P. 137-9? (d).Analysis indicated that it was probably a sulphuric acid salt of' thefree 'compoundaIX containing some water-0f crystallisation,- 1 U i V 1 1EXAMPLE 2 Preparation of pure compound IXA This can either be obtainedby separating a mixture of compounds IXA and IXB via theirhydrochlorides (method (a) below) or by carrying out the initialreaction under conditions where compound D(A hydrochloride alonecrystallises from the reaction mixture (method (b) below). u t w t (a)The mixture of compounds IXA and IXB isomers 3.41 g.) obtained from themother liquors of the preparation of pure IXB (see above) was suspendedin industrial methylated spirit. (25 m1.) and saturated ethanolichydrogen chloride added till the pH was 1.0.

' .The reaction mixture was allowed to stand at for 1% hours, and theresulting solid filtered. It was then refluxed for mins. in industrialmethylated spirit. (20 ml.) and the resulting suspension filtered andthe solid dried to give the bis-hydrochloride of compound IXA M.P. 2023(d).

This hydrochloride was dissolved in Water ml.) and the pH adjusted to10.0 by the addition of aqueous sodium carbonate.

The resulting white solid was filtered, washed with water and dried togive pure compound IXA M.P. 140-142.

Found: C, 68.09; H, 7.07; N, 6.44%. C H O N requires C, 68.17; H, 7.32;N, 6.36%.

(b) 6:7-dimethoxy-3:4-dihydroisoquinoline g.) was dissolved inindustrial methylated spirits (17 8 ml.) and ethanolic hydrogen chlorideadded to pH 5.8. Acetone dicarboxylic acid (5.89 g.) was added, followedby pyridine (15 ml.). Carbon dioxide was rapidly evolved and a whitesolid was precipitated. After hrs. the latter was filtered ofi, washedwith industrial methylated spirits and dried at room temperature invacuo.

(0) 3:4 dihydro 6:7 dimethoxyisoquinolinehydrochloride (1.0 g.) wasdissolved in industrial methylated spirit (10 ml.) and acetonedicarboxylic acid (0.33 g.) followed by pyridine (1.0 ml.) added. Themixture was allowed to stand at room temperature for 2 hours duringwhich time a solid separated from solution. Saturated ethanolic hydrogenchloride was added to bring the pH to 1.0, and the solid was thenfiltered, washed with cold industrial methylated spirit and dried togive pure compound IXA bis-hydrochloride 0.41 g. (37% theory) M.P.201-2", identical with the material obtained in method (a) above.

, Found: C, 58.05; H, 6.62; N, 5.53; Cl, 13.52%. C H O N Cl requires C,58.47; H, 6.57; N, 5.46; Cl, 13.81%.

EXAMPLE 3 Preparation 0 the N :N-butyryl derivative of compound IXB Purecompound IXB (10.92 g.) was dissolved in a mixture of anhydrous pyridine(33 ml.) and butyric an hydride (44 ml.). After standing at roomtemperature for 3 hours, the reaction mixture was poured into a solutionof sodium carbonate (45 g.) in water (900' ml.). The oil initiallyprecipitated solidified after standing (with occassional scratching) for1 hour and the mixture was allowed to stand overnight at roomtemperature. The solid was filtered, washed with water, and dried togive the dibutyryl derivative of compound IXB, 12.55 g. (99% theory)M.P. 133- 5". I 7

Found: H, 7.43; N, 4.46%. C H O N 1'6- quires C, 68.27; H, 7.64; N,4.83%.

Dry B precursor (13.71 g.) can also be converted direct l y to thedi-butyryl derivative of compound IXB in exactly the same way to give11.72 g. M.P. 133-5 EXAMPLE 4 Preparation of di-butyryl derivative ofcompound IXA Purec-ompound IXA (0.25 g.) was treated with butyricanhydride in pyridine exactly as for compound IXB to 12 give 0.29 g. ofthe dibutyryl derivative M.P. 169-17 1.

Found: C, 68.41; H, 7.46; N, 4.93%. C H44OqN2 requires C, 68.27; H,7.64; N, 4.83%.

EXAMPLE 5 Conversion of compound IXA into precursor of compound IXBCompound IXA (1 g.) was added to .a solution of cone. sulphuric acid(0.12 ml.) in water (12 ml.). The mixture was stirred and after 1 hourdiluted with an equal volume of water. The suspension was allowed tostand for 20 hours at room temperature, filtered, washed with water anddried at room temperature in vacuo. The solid was shaken with methylenechloride (10 m1.) filtered off, and re-dried to a white powder.

Wt.=0.9 g. M.P. 141-142 (decomp.)

Butyrylation of this material (0.25 g.) gave butyryl compound IXB (0.24g.) M.P. 133136.

EXAMPLE 6 The preparation of compound IX from 6:7-dimethoxy-3:4-dihydroisoquinoline and acetone 3 :4-dihydro-6 7-dimethoxyisoquinolinehydrochloride (IX hydrochloride; 0.5 g.) was dissolved in industrialmethylated spirit (10 ml.) and acetone (0.08 ml.) and pyridine (1.0 ml.)added. The mixture was allowed to stand at room temperature for 5 days,with occasional scratching. A white solid separated during this period.This was filtered, washed with industrial methylated spirits and driedat room temperature in vacuo to give 0.03 g. (4.8% theory) of compoundIXA hydrochloride, M.P. 199-200". Identity was proved by mixed M.P. andinfrared spectrum.

EXAMPLE 7 Preparation of 6 7-dimethoxy-1 :2 :3:4-tetrahydroisoquinol-I-yl acetone hydrochloride (a) From acet0ne.67-dimethoxy-3 :4-dihyd'roisoquinoline hydrochloride (0.5 g.) wasdissolved in industrial methylated spirits (10 ml.) with pyridine (1ml.) and acetone (10 ml.). The mixture was allowed to stand at roomtemperature for 3 days with occasional scratching. The yellow solutiongradually became orange and deposited white crystals which were filteredoff, washed with a little industrial methylated spirits and dried invacuo at room temperature.

Wt.=0.33 g. (55%), M.P. 18ll82 (decomp.).

(b) From acetoacetic ester.Acetoacetic ester (4.48 ml.) was added towater (35 ml.) containing sodium hydroxide (1.39 g.). The mixture wasallowed to stand at room temperature overnight and concentratedhydrochloric acid (2.56 ml.) added.

6:7-dimethoxy-3:4-dihydroisoquinoline (6 g.) was dissolved in methanol(12 ml.), water (13 ml.) was added and the two solutions were mixedtogether. The solution, after standing overnight at room temperature wastreated with aqueous sodium carbonate solution to pH 10, extracted asusual with methylene chloride (3X 50 ml.) and the extracts .washed withwater (3 X ml.). Removal of the solvent in vacuo gave an orange oil(7.65 g.). This was dissolved in industrial methylated spirits (22 ml.)and ethanolic hydrogen chloride added to pH 1. On scratching andcooling, a pale solid separated which was filtered off, washed with alittle industrial methylated spirits and dried at room temperature invacuo.

13 Wt.=7.l4 g. (ca. 80%). M.P. 184-185 (decomp.)."

. EXAMPLES Preparation of 1,3-bis(1 :2 :3 :4-tetrahydr0-6:7-dimethoxy- 2(3-0x0-but-1-yl)-is0quin0l 1-yl) acetone hydrochloride (compound XIIhydrochloride) (a) From compoundlXA and methylvinyl ketone C-ompound IXA(1 g.) in methylene chloride (25 ml.) was treated with methyl vinylketone (0.35 g.), and allowed to stand overnight at room temperature.The solvent was removed by distillation at roorn temperature in vacuo,and ether added and the Solvent again evaporated to give a pink'froth.This was dissolved in industrial methylated spirits (10 ml.) andethanolic hydrogen chlo ride added to pH 1. An immediate whiteprecipitate of the desired product was formed. After 1 hr..intherefrigerator, the. White solid was filtered off, washed with industrial methylated spirits and dried at room temperature. in vacuo. v

Wt.=0.95 g. M.P. 185-1-86 (decomp.)

Found: C, 57.74%; H, 7.05%; N, 3.92%,Cl, 9.87%. C33H4 07N2Cl2.2H2Orequires H, N, 4.06%; Cl, 10.28%. N 3

The free base had M.P. 1057 C.

wt.=,0.75 g. M.P. 121-124 (decomp).

Found: C, 53.39%; H, 7.34%; N, 3.60%; Cl, 10.16%. C33H4O7N2C12.5H20requires: C, H, N, 3.77%; CI, 9.54%.

EXAMPLE 9 Preparation of 1 :2 :3 :4-tetrahydro 6 :Z-dimethoxy 2-(3-oxo-but-I-yl)-is-quin0l-1-yl acetone hydrochloride 122:3 :4-tetrahydro6:7-dimethoxy-isoquinol l-yl aces tone (1.24 g.) was dissolvedinmethylene chloride (25 ml.) with methyl vinyl ketone (0.35 g.-), andallowed to stand overnight at room temperature. Evaporation of thesolvent at room temperature in vacuo, followed by treatment with etherand removal "of the solvent gave a pale yellow froth. 1 This wasdissolved =in-industrial methylated spirit (15 ml.) and alcoholichydrogen chloride added to pH 1. The mixture was diluted with ether (90ml.) and industrialmethylated spirits added till the gumminess in theprecipitate was discharged. The mixture was allowed to stand intherefrigerator with scratching overnight when the solid was removed byfiltration, washed with;.ether and dried at room temperature in vacuo.

, Wt.=1.0l g. M.P. 65 68 Found: 'C, 52.43%; H, 8.06%; N, 4.06%. I I v.C1s 2e 4 1- 2 requires C, 52.62%; H, 7.85%; N, 3.41%.

a EXAMPLEIO Preparation '01 3-aeetyl-1 :2 :3 :4 :6 :7-hexahydr0-1 113[H] 9:10-dimeth'oxy' 2'-methyl-benzo-[u]-quin0lizine 2-0l hydrochlorid'eI z (a) Sodium methoa cide' cyclisatio'n.-1 2 3.4-tet-rahy dro-6 7-dimethoxy-2- 3-oxobutyl -i s oquinol-1-yl acetone hydrochloride (1 g.)was converted into the free base by treatment with aqueous sodiumcarbonate solution. This was dissolved in benzene (30 ml.) and. a.solution of sodium methoxide (0.3 g.) in methanol (5 ml.) and industrialmethylated spirits (2 ml.) added. The mixture was shakenov'ernight atroom temperature when a pale orange solution was obtained. This waswashed with water (3X 25 ml.), the washed-being. back-extracted withbenzene (20 ml.). The benzene was removed invvacuo and the residue wasdissolved in industrial methylated spirits 10 ml.). .Ethanolic hydrogenchloride wasadded to .pH 1 and a white solid rapidly separated onscratching. After 1 hour in the refrigerator this' was filtered-off,washed with industrial methylated spirits and dried at room temperaturein vacuo.

' Wt.=0.6 g. M.P. 235-236 (decomp).

(b) Cyclisation with hydrochloric acid.1:2:3:4-tetrahydro-6:7dimetlioxy-isoquinol-1-yl acetone 2.68 g.) was dissolved in benzene ml.)and methyl vinyl ketone (0.7 g.) added. The mixture was allowed tostand. overnight at room temperature before the. solvent was removed.The residue was taken up in industrial methylated spirits. (50 ml.) andethanolic hydrogen chloride (-j2 ml.) added. After ca. 30 min.crystals'began to separate and the process was completed by alfurtherstanding. for 2 hours in'lthe refrigeraton. The crystals were filteredoif and dried in vacuo' at room temperature.

Wt.=l.84 M.P. 231 (decomp) Found: C, 60.6%; H, 7.56%. C H O NCl requiredC, 60.8%, H, 7.4%. I

The hydrochloride was basified with 1- N sodium hydroxide solution togive a red oil. This was-dissolved in a small amount of ether andreduced to a small volume by evaporation in vacuo without heating. Onscratching a pink solid separated. This was filtered oif (M.P.101.5-102) and recrystallised from ether/petroleum ether (B.P. 40-60")t'o l give'a pink crystalline solid M.P. 1035-1045". :1 r

Found: C, 67.26%; H, 8.06%; N, 4.53%., requires C, 67.7%; H, 7.9%;151,43%.

" I i.EXAMPLE11 Self-condensation of "1 E 3 -bis(2 I5uty ryl- 1 2:3z4-tetrahydro-6:7-dimetlioxyisoq'uinoi 1 iyl)acet0ne (ComfDibutyryhcompound (16.1 g.) in dry benzene (250 ml.) was added to asolution of sodium (3.2 g.: 5.0 mol) in dry ethanol, (ca. 50 ml.)and'the mixture was refluxed under nitrogen for 5* hours. When cool thesolution was diluted with benzene'and washed successively with water, 2N-hydrochloricacid, and water. The dried solution (MgSO an evaporationat diminished pressure, afforded ayellow glass- (13';2i g.),-which wasdissolved in a small volume of benzene and adsorbed on alumina (P.Spence, (Grade H) 800 g.), which had previously been neutralized anddeactivated by the dropwise addition of 10% aqueous a'ceticacid (40 ml.)to a stirred suspension in benzene. The chromatogram was elutedsuccessively with benzene (fractions 1-11), 5% ethyl acetate-benzene(F12-46), 10% ethyl acetate-benzene (F47-55), 15% ethyl acetate-benzene(F56-86), 20% ethyl aceate-benzene (F87-102), 40% ethyl acetatebenzene(F103-130), and finally with ethyl acetate (F131--145).

Fractions 10-70' (6.7 g.) contained mainly non-ketonic material, whichon,.fractional trituration with ether and recrystallisation from ethylacetate afforded 3-ethyl-1 :4: 6:7-tetra1hydr0-9:10-dimeth0xy-2 (2Tbutyryl 1'12 :3: 4'-tetrahydro-6':7'-dimethoxyisoquinol-1' yl) methyl- 4oxo-11BH-benzo[u]; guinolizine (Compound XI) M.P. 2112-203 from ethanol.4 k (Found: C, 70.08; H','7. 6 2; N, 5.09%. C H., O N requires c, 70.45;11,753; N,4.98%) 'U.v. maximum Cm sOi (EtOH) at 281 m (e=9800) andminimum at 258.5 mu (e=5700.), and a smaller yield of the more 3-ethyl-2:3: 6:7-tetrahydro-9:JO-a'imethwcy 2(2' butyryl-1:2:3: 4 tetrahydro6':7' dimethoxyisozjuinol-I'-yl)methyl- 4-oxo-4H-benz0[a]quinolizine(Compound XIA) M.P. 1 67168.5 (ex. ethyl aceate). (Found: C, 70.57;70.31; H, 7.23, 7.29; N, 5.23, 5.19; C H O N requires C, 70.45; H, 7.53;N, 4.98%), U.V. maxima (EtOH) at 250 m 280 III 1., 290 m (shoulder) and310 mp. (e=16600, 12600, 11700, and 9400).

Fractions 70 to 98 (2.95 g.) consisted mainly of unchangeddibutyrylketone contaminated with a small proportion of theanti-unsaturated amide.

Fractions 99 to 109 (0.71 g.) contained 3-ethyl-1z2z3: 4:6:7 hexahydro 2hydrxy-9:10-dimeth0xy-2-(2'- butyryl-1'z2' 3':4'-tetmhydro 67-dimeth0xyis0quin0l- 1-yl)mrethyl 4 oxo-IlbH-benzoh]quinolizine(Compound XIB) M.P. 206208 (ex. ethyl acetate). (Found: C, 68.58; H,7.62; N, 4.86%. C H O N requires C, 68.27; H, 7.64; N, 4.83%). U.V.maximum (EtOH) at 282.5 m (e=8000).

Fractions 110 to 145 (1.40 g.) contained 3-ethyl-6z7- dihydro 9:10dimethoxy-4-0x0-2(2'-fi-butyrylamin0- ethyl4':5-dimethoxy-fl-phenethyl)-4H-benzo[a]quinolizine M.P. 174175 (ex.ethyl aceate). (Found: C, 70.20, 70.34; H, 7.57, 7.36; N, 5.11, 4.8%.M01. Wt. 548,539. C H O N requires C, 70.43; H, 7.53; N, 4.98%. M01. wt.562). UV. maxima (EtOH) at 268 III/1., 283 m (inflexion) and 347 m(e=ll,000, 6,200, and 22,000). m

The 'yzfi-unsaturated amide (III) became the major condensation productat higher reflux temperatures (e.g. toluene), or with longer reactiontimes, e.g. 3 days) or when potassium t-butoxide was employed as thecondehs'ing agent.

EXAMPLE 12 3 acetyl 1,4,6,7-tetrahydr0-9,10-dimethoxy-Z-methyl-11b[H]-benz0[a]-quinolizine (VIII, R=H, R =CH R =Et)3-acetyl-1,2,3,4,6,7-hexa]1ydro-11b [H] 9,10 dimethoxy-2methylbenzo-[a]-quinolizine-2-ol hydrochloride (2.6 g.) was dissolved inconcentrated hydrochloric acid. After 3 hours at room temperature and 1hour at 100 C., the mixture was cooled, neutralized with potassiumcarbonate, and the base extracted with benzene. The residual gumobtained on evaporation of the solvent was dissolved in ethanol andtreated with ethanolic hydrogen chloride. The hydrochloride separated oncooling overnight.

Wt.='1.17 g. M.P. 221 C. Found: C, 63.81; H, 7.48; N, 3.90; CI, 9.92. CH O NC1 requires C, 64.01; H, 7.16; N, 4.15; Cl, 10.50%.

no. in ethanol max. 232 m Eiz =484, 281 my EXAMPLE 13 3 acetyl1,2,3,4,6,7 hexahydro-Z-hydroxy 9,10-dimethoxy2-[I,2,3,4-tetrahydr0-6,7-dimeth0xy-2-(3-0x0- butyl)isoquin0l-1-methyl]-I1b[H]-benz0-[a]-quinolizine (Compound XIIIa) BSERIES evaporated to dryness. Trituration of the residual gum with ethergave a solid (7.24 g.). This is essentially cyclic alcohol -Bcontaminated with some A isomer. Treatment of the mixture in ethanolwith hydrogen chloride precipitated the A isomer hydrochloride (seebelow). Addition of ether to the mother liquors gave the B isomerhydrochloride (5.75 g.) M.P. 192-3. Found: C, 56.27; H, 7.32; N, 3.74;Cl, 10.22.

requires C, 56.00; H, 7.41; N, 3.96; Cl, 10.02%.

The free base had M.P. 1568 C. Found: C, 68.25; H, 7.99; N, 5.03. C H ON requires C, 68.25; H, 7.63; N, 4.82%.

' A SERIES Compound (XIIA) hydrochloride (12.0 g.) was treated exactlyas above. The hydrochloride of cyclic alcohol A (4.8 g.) crystallisedfrom ethanol, M.P. 1989 C. Found: C, 58.84; H, 7.29; N, 4.32; Cl, 10.43.C H4 OqN2Cl2.H2O requires C, 59.01; H, 7.24; N, 4.02; C1, 10.56%.

The free base :had M.P. 1 60-2" C. Found C, 68.05; H, 7.72; N, 4.98. C HO N requires C, 68.25; H, 7.63; N, 4.82%.

EXAMPLE 14 3-acetyl-1,4,6,7-tertrahydr0 9,10 dimeth0xy-2-[1,2,3,4-tetra/1ydr0-6,7-dimeth0xy-2 (3 ox0butyl)-is0quin0l-I-methyl]-11b[H]-benz0[ot]-quin0lizine (XIII) B (SERIES Cyclic alcohol Bhydrochloric (10.31 'g.) Was heated at C. for 3 hrs. in 11 N-sulphuricacid (52 ml.). The cooled solution was basified with potassiumcarbonate, and the base extracted into benzene. The gum obtained onevaporation of the benzene solution was dissolved in N-hydrochloric acid(50 ml.) and treated with potassium iodide (8.5 g.) in Water ('15 ml.).The hydriodide of the product separated as a yellow powder, 9.05 g. M.P.190 C. (d). Found: C, 47.58; H, 5.64; N, 3.07; I, 29.61. C H O= N 2HLH Orequires C, 47.39; H, 5.54; N, 3.35; I, 30.34%.

A SERIES Cyclic alcohol A hydrochloride (6.59 g.) was dehydrated in 11N-sulphuric acid as above. In this case, trituration of the gumremaining after evaporation of the benzene with ether gave the freebase, 4.5 g. M.P. 1312 C. Found: C, 68.13; H, 7.64; N, 4.86.

33 42' s 2- 2 requires C, 68.25; H, 7.63; N, 4.82%.

The hydrochloride has M.P. C. (d). Found: C, 60.59; H, 7.03; N, 3.48;Cl, 10.14.

c l-n o N znctn o requires C, 60.64; H, 7.09; N, 4.29; Cl, 10.85%.

EXAMPLE 15 6: 7 -dimethoxy-1 ,2,3 ,4-tetrahydr0-is0quin0l- 1-yl-acet0acetic rzci d 6,7-di-methoxy-3,4-dihydroisoquinoline (24 g.)was dissolved in methanol (48 m1.) and'water (192 ml.). The mixture wascooled to below room temperature in cold water, and a solution ofacetone dicarboxylic acid (18.5 g.) in water '(48 ml.) added. After 2 /2hr..with continuous cooling and occasional shaking the fine white solidwas filtered, Washed with water, industrial methylated spirits andfinally With ether. After drying in vacuo at room temperature, theproduct weighed 19.2 g. M.P. 101-3 (decomp.). (Found: C, 60.92; H, 6.56;N, 4.57. C H O N requires C, 61.42; I-I, 6.53; N, 4.78%).

Weclaim:

1. A pr ess for the preparation of a benzoquinolizine,

17 which comprises reacting a 1 -substituted1,2;3,4-tetrahydroisoq-uinoline of, the .formula in which R is selectedfrom the group consisting of allcyl having -1 to 3 carbonatoms andl,2,3,4-tetrahydroiso quinol-l-yl-methyl [with a compound of the formula"R CO-CH=CH where R is alkyl having 1 to3 carbon .atomslan d cyclizingthe resulting product to produce a benzoquinolizine of the formula inwhich R has the above meaning and R is selected from a group consistingof alkyl having 1 to 3 carbon atoms and where R has the above meaning,said tetrahydroisoquinoline and said benzoquinolizine each beingsubstituted with at least one lower a-lkoxy group. I

2. A process as claimed in claim 1 in which the starting material is acompound of the formula CHaO 3. A process as claimed in claim 1 in whichR is 1,2, 3,4-tetrahydroisoquinol-1-ylmethy1 group and the cyclizationis effected with an alkaline reagent under mild conditions.

4. A process as claimed in claim 1 in which the starting compounds arein the same stereoisomeric series as natural emetine.

5. A process for the production of a benzoquinolizine comprisingreacting 3,4-dihydroisoquinoline with a compound of the formula where R"is a member selected from the group consisting of carboxyl and hydrogenand :R' is a member selected from the group consisting of alkyl having 1to 3 carbon atoms and carboxymethyl to form a l-substituted1,2,3,4-tetrahydroisoquinoline of the formula .p I where R is a memberselected from the group consisting of alkyl having 1 to 3 carbon atomsand 1,2,3,4-

'tetrahydroisoquinol-l-yl-methyl, reacting saidl-substitutedtetrahydroisoquinoline with a compound of the formula RCOCH=CH where R is alkyl having 1 to 3 carbon atoms and cyclizing theresulting product to form a compound of the formula COR ' HO R3 where Rhas the above meaning and R is selected from the group consisting ofalkyl having one to three carbon atoms and where R" is a member selectedfrom the group consisting of carboxylic and hydrogen and R' is a memberselected from the group consisting of alkyl having 1 to 3 carbon atomsand carboxymethyl to form a l-substituted 1,2,3,4-tetrahydroisoquinolineof the formula where R is a member selected from the group consisting ofalkyl having 1 to 3 carbon atoms and 1,2,15,4-tetrahydroisoquinol-l-yl-methyl, reacting said l-substit-utedtetrahydroisoquinoline with a compound of the formula where R is alkylhaving 1 to 3 carbon atoms and cyclizing the resulting product to form acompound of the formula HO R where R has the above meaning and R isselected from the group consisting of al-kyl having 1 to Scarbon atomsand N-C HzCHzO O R where R has the above meaning, and then dehydratingsaid compound to form a 2(3) double bond, each of the aromatic rings ofsaid dihydroisoquinoline, tetrahydroisoquinoline and benzoquinolizinepossessing at least one lower alkoxy substituent.

8. A process as claimed in claim 7 in which the dehydration is effectedin the presence of strong sulphuric acid.

9. A benzoquinolizine of the formula COR References Cited by theExaminer UNITED STATES PATENTS 3,103,835 10/1963 Walker et al 260-288ALEX MAZ'EL, Primary Examiner. NICHOLAS S. RIZZO, HENRY R. JIL-ES,Examiners.

DON KERR, DONALD G. DAUS,

i A I Assistant Examiners.

1. A PROCESS FOR THE PREPARATION OF A BENZOQUINOLIZINE, WHICH COMPRISESREACTING A 1-SUBSTITUTED 1,2,3,4-TETRAHYDROSIOQUINOLINE OF THE FORMULA9. A BENZOQUINOLIZINE OF THE FORMULA